An Effort at Improving Reliability of Laboratory Data in Titrimetric Analysis for Zinc Sulphate Tablets Using Validated Spreadsheet Calculators

Authors: M. A. Okezue, K. L. Clase, S. R. Byrn

Abstract:

The requirement for maintaining data integrity in laboratory operations is critical for regulatory compliance. Automation of procedures reduces incidence of human errors. Quality control laboratories located in low-income economies may face some barriers in attempts to automate their processes. Since data from quality control tests on pharmaceutical products are used in making regulatory decisions, it is important that laboratory reports are accurate and reliable. Zinc Sulphate (ZnSO₄) tablets is used in treatment of diarrhea in pediatric population, and as an adjunct therapy for COVID-19 regimen. Unfortunately, zinc content in these formulations is determined titrimetrically; a manual analytical procedure. The assay for ZnSO4 tablets involves time-consuming steps that contain mathematical formulae prone to calculation errors. To achieve consistency, save costs, and improve data integrity, validated spreadsheets were developed to simplify the two critical steps in the analysis of ZnSO4 tablets: standardization of 0.1M Sodium Edetate (EDTA) solution, and the complexometric titration assay procedure. The assay method in the United States Pharmacopoeia was used to create a process flow for ZnSO₄ tablets. For each step in the process, different formulae were input into two spreadsheets to automate calculations. Further checks were created within the automated system to ensure validity of replicate analysis in titrimetric procedures. Validations were conducted using five data sets of manually computed assay results. The acceptance criteria set for the protocol were met. Significant p-values (p < 0.05, α = 0.05, at 95% Confidence Interval) were obtained from students’ t-test evaluation of the mean values for manual-calculated and spreadsheet results at all levels of the analysis flow. Right-first-time analysis and principles of data integrity were enhanced by use of the validated spreadsheet calculators in titrimetric evaluations of ZnSO₄ tablets. Human errors were minimized in calculations when procedures were automated in quality control laboratories. The assay procedure for the formulation was achieved in a time-efficient manner with greater level of accuracy. This project is expected to promote cost savings for laboratory business models.

Keywords: Data integrity, spreadsheets, titrimetry, validation, zinc sulphate tablets.

References:

[1] Lowry A. Maintaining Lab Data Integrity: This article explores lab data integrity violation trends, as well as a sampling of the latest technologies that can help avoid them. Pharmaceutical Technology. 2018;42(2):28.
[2] Guidance on good data and record management practices (GDRP), (2016).
[3] World Health Organization. WHO | Zinc supplementation and growth in children: World Health Organization; 2019 updated 2019-02-11 09:30:38. Available from: https://www.who.int/elena/titles/zinc_stunting/en/. Accessed 20 December 2019
[4] World Health Organization. WHO | Zinc supplementation in the management of diarrhea: World Health Organization; 2019 updated 2019-02-11 09:28:35. Available from: https://www.who.int/elena/titles/zinc_diarrhoea/en/. Accessed 20 December 2019
[5] Rudan I, O'Brien KL, Nair H, Liu L, Theodoratou E, Qazi S, et al. Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries. J Glob Health. 2013;3(1):010401.
[6] Sakulchit T, Goldman RD. Zinc supplementation for pediatric pneumonia. Canadian Family Physician. 2017;63(10):763.
[7] Barnard DL, Wong M-H, Bailey K, Day CW, Sidwell RW, Hickok SS, et al. Effect of oral gavage treatment with ZnAL42 and other metallo-ion formulations on influenza A H5N1 and H1N1 virus infections in mice. Antiviral Chemistry and Chemotherapy. 2007;18(3):125-32.
[8] Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. The lancet. 2020;395(10224):e35-e6.
[9] Sarma P, Prajapat M, Avti P, Kaur H, Kumar S, Medhi B. Therapeutic options for the treatment of 2019-novel coronavirus: An evidence-based approach. Indian Journal of Pharmacology. 2020;52(1):1-5.
[10] Khalid Mahmood and Syeda Ailia Z. Short Communication - Over view for the truth of COVID-19 pandemic: A guide for the Pathologists, Health care workers and community'. Pakistan Journal of Medical Sciences. 2020;36(S4):S111.
[11] Worsfold P, Townshend A, Poole CF, Miró M. Encyclopedia of Analytical Science: Titrimetry Overview. Encyclopedia of analytical Science: Elsevier lLtd.; 2019.
[12] Valcárcel M, Luque de Castro MD. 13 Automatic titrators: Elsevier; 1988. Pages 393-427 p.
[13] Guide MTT. Titration Guide on errors: How to identify and avoid titration errors Switzerland: Mettler-Toledo International Inc.; 2015 Available from: https://d3pcsg2wjq9izr.cloudfront.net/files/2317/download/661751/titration_guide_EN.pdf.
[14] Titrations.info. Titration and titrimetric methods - sources of errors 2011 Available from: http://www.titrations.info/titration-errors. Accessed 20 June 2020
[15] Al Alawi AM, Majoni SW, Falhammar H. Magnesium and Human Health: Perspectives and Research Directions. Int J Endocrinol. 2018;2018.
[16] WG Critical Care L. DailyMed - Magnesium Sulfate injection: Drug Information label USA: NIH-National Library of Medicine; 2019 Available from: https://www.ncbi.nlm.nih.gov/pubmed/.
[17] DailyMed. DailyMed - Calcium Gluconate injection, solution: Drug label information USA: NDC Code(s): 63323-360; 2019 Available from: https://www.ncbi.nlm.nih.gov/pubmed/. Accessed 20 June 2020.
[18] World Health Organisation. WHO: Zinc supplementation in the management of diarrhea: World Health Organization; 2019 updated 2019-02-11 09:28:35. Available from: https://www.who.int/elena/titles/zinc_diarrhoea/en/. Accessed 20 June 2020.
[19] Okezue M, Clase KL, Byrn S. Use of Excel Spreadsheet Calculators in Handling Data Generated From UV- Spectrometer. BIRS Symposium. 2018.
[20] Choy KW. Automated spreadsheets minimise laboratory error and improve analysis time in molecular haematology testing. Pathology. 2019;51:S119.
[21] Fasoula S, Nikitas P, Pappa-Louisi A. Teaching simulation and computer-aided separation optimization in liquid chromatography by means of illustrative Microsoft Excel spreadsheets. ACS Publications; 2017.
[22] USP-NF USP. USP-42 / NF-37 Monograph: Zinc Sulfate Tablets 2019 Available from: https://online.uspnf.com/uspnf/document/GUID-65B8F818-E5BD-4BC7-8B00-40349B7F547E_1_en-US.
[23] WHO. The International Pharmacopoeia Ninth Edition. Monographs: Dosage forms: Specific monographs: Pediatric zinc sulfate tablets Geneva2019 Available from: https://apps.who.int/phint/en/p/docf/anchor,reading-docs.html. Accessed 13 November 2020.
[24] Sandell EB, West TS. Recommended nomenclature for titrimetric analysis. Pure and Applied Chemistry. 1969;18(3):427-36.
[25] Ferreira D, Barros M, Oliveira CM, da Silva RJNB. Quantification of the uncertainty of the visual detection of the end-point of a titration: Determination of total hardness in water. Microchemical Journal. 2019;146:856-63.
[26] Kimaru I, Corigliano AZ, Fang. Using Classical EDTA Titrations To Measure Calcium and Magnesium in Intravenous Fluid Bags. Journal of Chemical Education. 2019.
[27] Alibaba.com. titrator price, titrator price Suppliers and Manufacturers at Alibaba.com: Submit RFQ Instant Quotes RFQ Sourcing Tool; 2019 Available from: https://www.alibaba.com/showroom/titrator-price.html. Accessed 29 November 2019.